ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1065G>A (p.Lys355=) (rs41286292)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111537 SCV000578264 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV001084435 SCV000075337 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000111537 SCV000154014 likely benign Breast-ovarian cancer, familial 1 2014-01-23 criteria provided, single submitter literature only
GeneDx RCV000159867 SCV000209920 benign not specified 2014-10-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000163137 SCV000213652 likely benign Hereditary cancer-predisposing syndrome 2014-09-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc RCV000163137 SCV000682932 benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586457 SCV000698829 benign not provided 2016-10-05 criteria provided, single submitter clinical testing Variant summary:The BRCA1 c.1065G>A (p.Lys355Lys) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splicing algorithms predict no significant effect on splice donor and acceptor sites, which is consistent with an in vitro study (Anczukow et al 2008) showing that the variant did not affect splicing based on a mini-gene assay. This variant was found in 23/121396 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003297 (22/66736). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), but suggests that it may be a rare polymorphism. In at least two reported patients (1 published and 1 unpublished finding from UMD), this variant co-occurred with another deleterious variant in BRCA1, strongly supporting a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, all evidence supports a non-pathogenic nature for the variant, and the variant was classified as benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111537 SCV000143994 benign Breast-ovarian cancer, familial 1 2000-08-09 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354009 SCV000591314 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Lys355Lys variant was identified in 2 of 4244 proband chromosomes (frequency: 0.000) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Ricevuto 2001). The variant was also identified in dbSNP (ID: rs41286292) “With other allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), Exome Variant Server project in 1 of 8599 European American alleles, the ClinVar database 4X (classified as benign (BIC and GeneDx), likely benign (Counsyl) and uncertain significance (Invitae)), GeneInsight VariantWire database (2X, classified as “predicted unlikely impact” by a clinical laboratory), the BIC database (2X with no clinical importance), and UMD (17X as an unknown variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (p.Val939LeufsX61), increasing the likelihood that the p.Lys355Lys variant does not have clinical significance. The variant was also identified by the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 22 of 66736 chromosomes (frequency: 0.0003297) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified by our laboratory in 2 individuals with breast cancer. The p.Lys355Lys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
MVZ Praenatalmedizin und Genetik Nuernberg RCV000111537 SCV000777896 likely benign Breast-ovarian cancer, familial 1 2018-05-01 no assertion criteria provided clinical testing This rare variant (gnomAD) was found multiple times in databases to be classified as uncertain or likely benign. Interestingly we found this variant in a patient who harbored also a pathogenic BRCA2-variant (NM_000059.3|c.1813dupA|het). Therefore we rate this variant as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735494 SCV000863632 benign Breast and/or ovarian cancer 2012-06-19 no assertion criteria provided clinical testing

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